MX2009001710A - Use of hppd inhibitors in the treatment of depression and/or withdrawal symptoms associated with addictive drugs. - Google Patents

Abstract

The present invention relates to, inter alia , the use of a compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal in the manufacture of a medicament for use in the treatment and/or prevention of depression. The invention also provides for the use of a compound capable of inhibiting HPPD in an animal in the manufacture of a medicament for use in the treatment of the withdrawal symptoms associated with an addictive drug which causes dopamine dependant associative learning disorders in said animal. In a particular embodiment said HPPD inhibitor is selected from the group consisting of the compound depicted as compound 1; 2; and 3.22.

Description

USE OF HPPD INHIBITORS FOR THE TREATMENT OF DEPRESSION AND / OR ABSTINENCE SYNDROME ASSOCIATED WITH ADDICTIVE DRUGS The present invention relates, inter alia, to the use of an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD) for the treatment of. depression and / or abstinence syndrome associated with an addictive drug that produces associative learning disorders dependent on dopamine. More specifically, the HPPD inhibitor is selected from the group consisting of: compound 1; compound 2 and compound 3.22.

Clinical depression is a state of sadness, melancholy or despair that has advanced to the point of being detrimental to the functioning and / or social activities of the individual in daily life. Currently, clinical depression is the leading cause of disability in the United States, as well as in other countries, and it is expected that by the year 2020 it will become the second leading cause of disability in the entire world (after coronary heart disease) , according to the World Health Organization.

The efficacy of antidepressants such as, for example, selective serotonin reuptake inhibitors (SSR1) and tricyclic antidepressants per se, is moderate and there is a therapeutic need for more effective therapies.

Therefore, it is convenient to provide a drug that can alleviate depression. Throughout this description, the term "depression" includes bipolar and unipolar disorders.

In general, the present invention seeks to provide, among other things, a drug for use in the treatment of depression that overcomes and / or ameliorates the problems mentioned herein.

Therefore, the present invention provides, among other things, compositions and methods of use for inhibiting 4-hydroxyphenylpyruvate dioxygenase in animals so as to achieve an increase in the synthesis and / or turnover of dopamine.

In accordance with the present invention, there is provided the use of at least one compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal, in the manufacture of a medicament for use in the treatment and / or prevention of depression. In a particular embodiment, said medicament comprises a compound selected from the group consisting of: compound 1; 2 and 3.22 as described herein. In a particular embodiment, said medicament comprises the compound represented as compound 1.

The present invention further provides the aforementioned use wherein said medicament comprises a selective serotonin reuptake inhibitor (SSRI) and / or a tricyclic (tricyclic) antidepressant. In a particular embodiment, said SSRI is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline or mixtures thereof and said tricyclic is selected from the group consisting of: amitriptyline, clomipramine, dosulepin, dotiepin, doxepin, maprotilina, mianserina, trazodona, trimipramina, amoxapina, imipramina, lofepramina and nortriptilina or mixtures of the same.

In a particular embodiment, said SSRI and the medicament comprising said HPPD inhibitor can be administered separately.

In a particular embodiment, said tricyclic and the medicament comprising said HPPD inhibitor can be administered separately.

The present invention further provides a kit comprising a pharmaceutically effective amount of a compound selected from the group consisting of: Compound 1; 2 and 3.22 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a selective serotonin and / or tricyclic antidepressant reuptake inhibitor and a means for administration to an animal.

The present invention further provides a pharmaceutical composition comprising, as an active ingredient, a pharmaceutically effective amount of a compound selected from the group consisting of compound 1; 2 and 3.22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a selective serotonin reuptake inhibitor and / or a tricyclic antidepressant together with a pharmaceutically acceptable diluent or carrier. In a particular embodiment, said SSRJ is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline or mixtures thereof, and said tricyclic group is selected from: amitriptyline, clomipramine, dosulepin, dotiepine, doxepin, maprotiline, mianserin, trazodone, trimipramine, amoxapine, imipramine, lofepramine and nortriptyline or mixtures thereof.

In another aspect, the present invention provides the use of HPPD inhibitors for the treatment of withdrawal syndrome associated with an addictive drug that produces associative learning disorders dependent on dopamine. These addictive drugs include: psychostimulants such as cocaine and amphetamine and also narcotic analgesics, opiate, nicotine, ethanol, tetrahydrocannabinol and phencyclidine.

Nicotine is a stimulant that temporarily improves alertness and memory, but also produces a strong chemical and physical dependence (addiction). Through the use of cigarettes, cigars and chewing tobacco, nicotine is one of the most widely used addictive drugs.

Medical research has determined that smoking is a major factor that causes many health problems, especially lung cancer, emphysema and cardiovascular disease. Many of the effects that tobacco produces on health can be minimized by quitting smoking.

Many smokers want to stop smoking but need to be assisted by pharmacotherapy since nicotine dependence is difficult to treat. Pharmacological options for the treatment of tobacco dependence are usually limited to nicotine replacement therapy and, more recently, to the use of sustained-release bupropion, which, per se, may have limited efficacy.

The present invention provides the use of an HPPD inhibitor which acts as, inter alia, a stimulant to increase the production of dopamine in the brain. This stimulating effect will be exploited as an aid to achieve abstinence from the use of tobacco products by reducing craving, lowering the brain reward threshold and alleviating some symptoms of nicotine withdrawal syndrome, including depressive mood, irritability, difficulty concentrating and Increased appetite Cocaine is an example of another addictive drug. Cocaine is a stimulant that creates what has been described as "feeling of euphoria of happiness" and "increased energy". Cocaine can produce physical and psychological dependence, hindering abstinence. Cocaine has become the second most widely used recreational drug in the United States.

At present, there are no approved or effective pharmacological agents to help patients addicted to cocaine quit. The severity of the withdrawal syndrome is one of the main reasons that the patient does not support abstinence. The invention provides, inter alia, the use of an HPPD inhibitor to increase the concentration or turnover of dopamine and, thus, reduce the adverse symptoms of cocaine withdrawal and increase the likelihood of successful abstinence.

Therefore, the present invention also seeks to provide, among other things, a drug for use in the treatment of the withdrawal syndrome associated with an additive drug that produces associative learning disorders dependent on dopamine, whose drug overcomes and / or improves the problems mentioned here.

In this way, the present invention provides, among other things, compositions and methods for its use as an inhibitor of 4-hydroxyphenylpyruvate dioxygenase in animals, so that an increase in the synthesis and / or turnover of dopamine is achieved.

The present invention, therefore, provides the use of at least one compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal, in the manufacture of a medicament for use in the treatment of withdrawal syndrome associated with an addictive drug. that produces associative learning disorders dependent on dopamine in said animal. In a particular embodiment, said addictive drug is a drug selected from the group consisting of: cocaine, amphetamine, opiate, nicotine, ethanol, tetrahydrocannabinol and phencyclidine. In a particular embodiment, said drug is nicotine. In another embodiment, said drug is cocaine.

The present invention further provides the use described above wherein said medicament comprises a compound selected from the group illustrated as compound 1; 2 and 3.22.

The present invention even further provides the use described above wherein the medicament comprises another compound that is also capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal.

Even, the present invention also provides the use described above wherein said medicament comprises a nicotine replacement therapy. Such nicotine replacement therapies are known in the art and include gums, patches, tablets, dragees, sprays and inhalers.

The present invention also provides the use described above wherein said medicament comprises bupropion.

The present invention additionally comprises the use described above wherein said medicament is used in conjunction with a nicotine replacement therapy.

Additionally, the invention provides the use described above wherein said medicament is used together with bupropion.

In a particular embodiment, said nicotine replacement therapy can be administered separately from the medicament comprising said HPPD inhibitor.

In a particular embodiment, said bupropion can be administered separately from the medicament comprising said HPPD inhibitor.

In addition, in another aspect, the present invention provides a kit comprising a pharmaceutically effective amount of a compound selected from the group consisting of: 1; 3.22 and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a nicotine and / or bupropion replacement therapy, and a means for administering it to an animal.

In yet another aspect, the present invention provides a pharmaceutical composition comprising as active ingredient a pharmaceutically effective amount of a compound selected from the group consisting of: Compound 1; 3.22 and 2 and a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a therapy of nicotine and / or bupropion replacement together with a pharmaceutically acceptable diluent or carrier.

The present invention even further provides a pharmaceutical composition described above having a form suitable for oral or parenteral administration.

The present invention further provides an additional pharmaceutical composition described above having pleasant taste suitable for oral administration selected from the group consisting of: tablets; pills; hard capsules; aqueous suspensions; oily suspensions; emulsions; dispersible powder; dispersible granules; syrups and elixirs.

The present invention also provides a pharmaceutical composition described above designed for oral use and has the form of hard or soft gelatin capsules.

The present invention also provides a pharmaceutical composition described above having the form suitable for parenteral administration.

In this manner, the compositions of said HPPD inhibitors for use in the invention may have various conventional forms known in the pharmaceutical art and which are especially adapted for pharmaceutical use, ie for administration to humans and other warm-blooded animals.

The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.

Thus, compositions designed for oral use will normally contain, for example, at least one or more coloring agents, sweeteners, flavorings and / or preservatives and may have the form of hard gelatin capsules in which the active ingredient is mixed with a inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. The compositions for oral use they can also be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as, for example, arachis oil, liquid paraffin or olive oil.

Pharmaceutically acceptable excipients for use in tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating or disintegrating agents such as, for example, corn starch or alginic acid; binding agents such as, for example, gelatin or starch; lubricating agents such as, for example, magnesium stearate, stearic acid or talc; preservatives such as, for example, ethyl or propyl p-hydroxybenzoate, and antioxidants, such as, for example, ascorbic acid.

The tablet formulations may or may not be coated, either to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance; in either case, the use of conventional coating agents and methods is well known in the art.

In general, aqueous suspensions will contain the active ingredient in fine powder form together with one or more pharmaceutically acceptable suspending agents, such as, for example, sodium carboxymethylceulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum.; dispersing or wetting agents such as, for example, lecithin or condensation product of an alkylene oxide with fatty acids (for example, polyoxyethylene stearate) or products of the condensation of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene oxyketanol or products of the condensation of ethylene oxide with partial esters derived from fatty acids and un'hexitol such as, for example, polyoxyethylene sorbitol monooleate or products of the condensation of ethylene oxide with partial esters derived from fatty acids and anhydrides. hexitol, for example, sorbitan monooleate.

Typically, aqueous suspensions will also contain one or more preservatives (such as, for example, ethyl or propyl p-hydroxybenzoate, antioxidants (eg, ascorbic acid), coloring agents, usually together with a flavoring and / or sweetening agent (e.g. saccharin or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (e.g., Arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (e.g., liquid paraffm).

The oily suspensions may also contain a thickening agent such as, for example, beeswax, hard paraffin or cetyl alcohol.

Sweetening agents such as those mentioned above and flavoring agents can be added to provide an oral preparation with a pleasant taste.

These compositions can be preserved by the addition of an antioxidant such as, for example, ascorbic acid.

In general, dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water, contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

In general, pharmaceutically acceptable excipients such as for example sweetening, flavoring and coloring agents will also be present.

The pharmaceutical compositions of the invention may also take the form of oil-in-water emulsions.

The oil phase may be a vegetable oil, such as, for example, olive or Arachis oil, or a mineral oil such as, for example, liquid paraffin or a mixture of any of them.

Suitable emulsifying agents can be, for example, gums of natural origin such as, for example, acacia gum or tragacanth gum, phosphatides of natural origin such as, for example, soybean, lecithin, or partial esters or esters derived from fatty acids and anhydrides. of hexitol (for example, sorbitan monooleate) and products of the condensation of said partial esters with ethylene oxide such as, for example, polyoxyethylene sorbitan monooleate.

The emulsions may also contain sweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, aspartame or sucrose and may also contain a demulcent, preservative, flavoring and / or coloring agent.

The pharmaceutical compositions may also take the form of a sterile injectable aqueous oil suspension ii which can be formulated according to known procedures, using one or more of the above-mentioned suitable dispersing or wetting agents and suspending agents.

A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable for parenteral use, for example, a solution in 1,3-butanediol.

Dosage The amount of active ingredient that is combined with one or more excipients to produce a simple dosage form, will necessarily vary according to the host treated and the particular route of administration.

In general, a formulation designed for oral administration to humans will contain, for example, between 0.01 mg to 10 mg of active agent per Kg of body weight combined with an appropriate and convenient amount of excipients.

The unit dosage forms will generally contain between about 0.1 and about 500 mg of an active ingredient.

More specifically, in general, a formulation comprising compound 2, for example, designed for oral administration to humans, will contain, for example, between 0.01 mg to 1 mg of active agent per Kg of combined body weight, with an amount of appropriate and convenient excipients.

The unit dosage forms for a formulation comprising compound 2 will generally contain between about 0.1 mg and about 100 mg of an active ingredient.

However, it will be readily understood that it may be necessary to vary the dose of the active ingredient administered according to the well-known medical practice according to the nature and severity of the condition or disease under treatment, any concurrent therapy and age, weight, genotype and sex. of the patient receiving the treatment.

In general, in therapeutic use, it is understood that a composition according to the invention could be administered so that the dose of the HPPD inhibitor (or an equivalent amount of a pharmaceutically acceptable salt thereof) is received, said dose generally it is comprised between 0.00002 to 10 mg / kg / day or 0.001 to 500 mg / day, more specifically, 0.05-10 mg / day and 0.1-5 mg / day or 0.01 to 10 mg of the active agent per kg body weight daily, divided into doses if necessary.

More specifically, for a composition comprising compound 3.22 or 2, in therapeutic use, it is contemplated that a composition according to the invention, would be administered so as to receive a dose of the HPPD inhibitor (or an equivalent amount of a pharmaceutically salt). acceptable thereof) that, in general, is between 0.0002 to 1 mg / kg / day, or 0.01 to 100 mg / day. More specifically, between 0.05 to 10 mg / day and 0.1 to 5 mg / day or 0.01 to 1 mg of the active agent per kg of body weight per day, if necessary in divided doses. All ranges expressed in this description are inclusive. For example, between 0.01 to 100 includes the values 0.01 and 100.

Intermittent dosing of the HPPD inhibitor (or a pharmaceutically acceptable salt thereof) may also be convenient.

In addition to the evaluation of the general condition of the patient, the effects of administration of the HPPD inhibitor can be controlled by standard clinical chemistry and blood tests.

In yet another aspect of the invention, there is provided a method for treating and / or preventing depression comprising administering to an animal a pharmaceutically effective amount of a compound selected from the group consisting of: Compound 1; 2 and 3.22 or a composition as described above.

Even in another aspect of the invention, there is provided a method for treating an animal suffering from withdrawal syndrome caused by addiction to a drug that is responsible for the development of associative learning disorders dependent on dopamine in said animal, said method comprises administering to said animal a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1, 3.22 and 2 or a composition as described above.

In a preferred embodiment of the invention, said animal is a human being.

The HPPD inhibitors that can be applied to the present invention include the compounds of the formula I (the term Formula 1 can be used interchangeably with Compound (I) (Compound I) where; T is T | where: G is C or N where, when G is N, then, only one of E and R2 are present; D is hydrogen or R3; E is hydrogen or R4; or D and E together are C2-C3 alkylene which may be mono- or polysubstituted with R6; A is Ci-C2 alkylene which may be mono- or polysubstituted with R5; or A can be, in addition, carbonyl, oxygen or -N-R7- where D and E are different from C2-C3 alkylene; Ri, R 2, R 3, R 4, R 5 and R 6 are each, independently of the others, hydrogen, C 1 -C 4 alkyl, phenyl, C 1 -C 4 alkoxy, halogen, hydroxy, cyano, hydroxycarbonyl or C 1 -C 4 alkoxycarbonyl; or R.2 and R4 together form a C2-C4 alkylene chain which may be interrupted by oxygen and / or carbonyl and / or sulfur, with the proviso that the oxygen and sulfur atoms are separated by at least one methylene group; R 7 is C 1 -C 4 alkyl, alkoxycarbonyl or C 1 -C 4 alkoxycarbonyl; R03 is hydroxy, 0"M +, where M + is an alkali metal or ammonium cation, halogen, alkylsulfonyloxy Ci -C | 2, amino, alkylthio C | -C, alkylsulfinyl C | -C! 2, alkylsulfonyl C | -Ci2 , C 1 -C 12 haloalkylthio, C 1 -C 2 haloalkylsulfinyl, C 1 -Ci 2 haloalkylsulfinyl, C 1 -C 6 alkyloxyCi-Ce alkoxy, C 1 -C 6 alkoxy Ci-C 6 alkylsulfinyl, C 1 -C 6 alkyloxy C 1 -C 6 alkylsulfonyl, C3-C12 alkenylthio, C3-Ci2 alkenylsulfinyl, C3-C2 alkenylsulfonyl, C3-C2 alkynylthio, C3-C12 alkynylsulfinyl, C3-C12 alkynylsulfonyl, C4-4alkylcarbonylalkyl, C4-4alkylcarbonylsulphite -C4, alkoxycarbonylCi-C4-alkylsulfonylCi-C4, (alkoxyC | -C4) 2P (0) 0, alkylC | C4- (alkoxyC, C4) P (0) 0, H (alkoxyC, -C4) P (0) 0 , R037R038N, R039R040NNH, Ro4 iRo42NC (0) 0-, Ro43Ro44NC (0) NH-, alkylcarbonyloxy Ci-C) 8, alkenylcarbonyloxy Ci-C | 8, alkynylcarbonyloxy C2-C |, cycloalkylcarbonyloxy C3- C6, or alquothiocarbamoyl C1-C12 , where the alkyl, alkenyl and alkynyl groups can be substituted with halogen , Ci-C6 alkoxy, alkylthio C | -C6, Cr C6 alkylsulfinyl, C | -C6 alkylsulfonyl, or by cyano; or R036 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino, phenylsulfonyloxy, benzoyloxy or benzoyl-d-C6alkoxy, wherein the phenyl groups may, in turn, be substituted one or more times with halogen, nitro, cyano, Ci-C4 alkyl, haloalkylC | -C4, C1-C4 alkoxy and / or C 1 -C4 haloalkoxy, or R () 36 is a group Het07-thio, Heto2-sulfinyl, Het09-sulfonyl, Hetoio- (CO) 0 or Heton-N (l7); where Het07, Het08, Het09, Hetoium and Heton are each, independently of the others, a ring system monocyclic or bicyclic ringed from five to ten members that can be aromatic or partially saturated, and can contain between 1 and 4 heteroatoms selected from nitrogen , oxygen and sulfur, and each ring system can contain no more than two oxygen atoms and no more than two sulfur atoms and the ring system itself can be substituted by C 1 -C alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, haloalkoxy Ci-C6, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, di (C 1 -C 4 alkylaminosulfonyl), di (C 1 -C 4 alkylamino), halogen, cyano, nitro or by phenyl, and the substituents in the nitrogen atom of the heterocyclic ring may be different from halogen; Ro37, Ro38, R03, R04o, RMI, Ro42, R043, 044 and R047 are, each independently of the others, hydrogen or C] -C6 alkyl; or R037 and o38 together or R039 and R04o together or R04 i and R042 together or R043 and R044 together, are pyrrolidino, piperidino, morpholino or thiomorpholino, which may be mono- or polysubstituted by methyl groups; or T is T2 where R 34 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or benzyl, it being possible for the phenyl group to be substituted one or more times with Ci-Co alkyl, Ci-C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C haloalkoxy, halogen, cyano, hydroxy and / or nitro; R 35 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl or benzyl, it being possible for the benzyl group to be substituted one or more times by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl , Ci-C6 alkoxy > haloalkoxy C | -C6 halogen, cyano, hydroxy and / or nitro; R36 is hydroxy, 0"M +, where M + is an alkali metal cation or ammonium cation, halogen, C1-C12 alkylsulfonyloxy, amino, C1-C4 alkylthio, alkylsulfinyl C | -C | 2 alkylsulfonyl C1-C12, haloalkylthio C1- C12, haloalkylsulfinyl C | -C | 2, haloalkylsulfonyl C | -C | 2, alkoxyC | -C6-alkylthioC | -C6, alkoxyCi-Ce-alkylsufinylCi-Co, alkoxy Ci-C6-alkylsulfonyl Ci-C6, alkenylthio C3-C 12, C3-C12 alkenylsulfinyl, C3-C12 alkenylsulfonyl, C3-C12 alkynylthio, C3-C2 alkynylsulfinyl, C3-Ci2 alkynylsulfonyl, alkoxycarbonylCi-C4-alkylthioCi-C4, alkoxycarbonylCi-C4-alkylsul finylC | -C4, alkoxycarbonylC | C 4 -alkylsulfonylC | -C 4, (C 1 -C 4 alkoxy) 2P (0) 0, C 1 -C 4 alkyloxy (C 4 alkoxy) P 0 0, H (C alkoxy, C 4) P 0, RcmRtmN, R 039R04oNNH, R04iR042NC (O) C-, R43 or 4C (0) NH-, C 1 -C 8 alkylcarbonyloxy, C 1 -C 8 alkenylcarbonyloxy, C 2 -Cis alkynylcarbonyloxy, C 3 -C 6 cycloalkylcarbonyloxy, or C 1 -C 2 alkylthiocarbamoyl, where the alkyl, alkenyl and alkynyl groups can be substituted with hal Oxygen, Ci-C6 alkoxy, Ci-C6 alkylthio, Ci-C6 alkylsulfinyl, C |-C6 alkylsulfonyl, or by cyano; or R36 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino, phenylsulfonyloxy, benzoyloxy or benzoyl-alkoxyC | -C6, it being possible for the phenyl groups, in turn, to be replaced one or more times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and / or C 1 -C 4 haloalkoxy , or R36 is a group Het7-thio, Hetg-sulfinyl, Het9-sulfonyl, Heti0- (CO) O or Hetu -? (? 7); where Het7, Hetg, Het9, Hetio and Hetu are independently of the others, a ring system monocyclic or bicyclic annular of five to ten members that can be aromatic or partially saturated, and can contain between 1 and 4 heteroatoms selected between nitrogen, oxygen and sulfur , and each ring system may contain no more than two oxygen atoms and no more than two sulfur atoms and the ring system itself may be substituted by Ci- C6 alkyl, C | -C haloalkyl, C | -C6 alkoxy, haloalkoxy C | -C6, Ci-C6 alkylthio, C |-C6 alkylsulfinyl, C |-C6 alkylsulfonyl, di (CC-C) alkyl aminosulfonyl, di (CC-C 4 alkyl) amino, halogen, cyano, nitro or by phenyl, and substituents in the nitrogen atom of the heterocyclic ring they may be different from halogen; R037, Ro38, Ro3, R04o > Ro4i, R042, R043 > 4 and 047 are, each independently of the others, hydrogen or Ci-C6 alkyl; or R037 and R038 together or R039 and R040 together or R04i and R042 together or R043 and R044 together, are pyrrolidino, piperidino, morpholino or thiomorpholino, which may be mono- or polysubstituted by methyl groups; or T is T3 R 4) is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl or halo substituted C 3 -C 6 cycloalkyl; Z0 | it is a chemical bond, S, SO or S02; or -C02- R 5 is hydrogen or C 1 -C 3 alkylene which may be substituted with the following substituents: halogen, hydroxy, C 6 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy C 1 - alkoxy C6, alkoxyCi-C6-alkoxyC | -C-alkoxyC | -C6, (3-oxethanyl) -oxi, (3-oxetanyl) -oxiCi-C6-substituted alkyl, benzylthio, benzylsulfinyl, benzylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, being possible for the groups containing phenyl and benzyl, in turn, be substituted by one or more C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, cyano, hydroxy and / or nitro group; or R5o is phenyl, it being possible for the phenyl-containing group, in turn, to be substituted by one or more Ci-C6 alkyl groups, C-C6 haloalkyl, Ci-C6 alkoxy, C | -C6 haloalkoxy, halogen, cyano, hydroxy and / or nitro; or R50 is C3-C6cycloalkyl, C6-C6 alkoxy or C3-C6 cycloalkyl-substituted C6-C6 alkyl, 3-oxetanyl or 3-oxetanyl-C6-substituted alkyl; or T is T4 where R045 is CrC6 alkyl, haloCi-Ce, C3-C6 cycloalkyl or halo-substituted C3-C6 cycloalkyl; and the pharmaceutically acceptable salts, isomers and enantiomers thereof.

The compounds of the formula I further include the salts which said compounds are capable of forming with amines, alkali metal and alkaline earth metal bases or ammonium bases quaternary. Among the alkali metal and alkaline earth metal hydroxides as salt formers, special mention must be made of the hydroxides of lithium, sodium, potassium, magnesium and calcium, but especially the hydroxides of sodium and potassium.

Examples of suitable amines for ammonium salt formation include ammonia as well as primary, secondary and tertiary C, -C] alkylamines, hydroxyalkylamines C | -C4, and C2-C4 alkoxyalkylamines, for example, methylamine, ethylamine, h-propylamine, isopropylamine, the four isomers of butylamine, n-amylamine, isoamylamine, hexylamine, heptylamine, octylamine, nonylamine, decyamine, pentadecylamine, hexadecylamine, heptadecylamine, octadecylamine , methylethylamine, methylisopropylamine, methylhexylamine, methylnonthylamine, methylpentadecylamine, methyloctadecylamine, ethylbutylamine, ethyheptylamine, ethylctylamine, hexylheptylamine, hexyloctylamine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, di-n-amylamine, diisoamylamine , dihexylamine, diheptylamine, dioctylamine, ethanolamine, n-propanolamine, isopropanolamine,?,? -ethanol amine, N-ethylpropanolamine, N-butylethanolamine, allylamine, n-butenyl-2-amine, n-pentenyl-2-amine, 2, 3-dimethylbutenyl-2-amine, dibutenyl-2-amine, n-hexenyl-2-amine, propylene diamine, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tri-sec-b utylamine, tri-n-amylamine, methoxyethylamine and ethoxyethylamine; heterocyclic amines, for example, pyridine, quinoline, isoquinoline, morpholine, piperidine, pyrrolidine, indoline, quinuclidine and azepine; primary arylamines, for example, anilines, methoxyanilines, ethoxyanilines, o-, m- and p-toluidines, phenylenediamines, benzidines, naphthylamines and o-, m- and p-chloroanilines; but especially, triethylamine, isopropylamine and diisopropyl amine.

As the compounds of Formula I where T is Ti, preferably have the enolized form or the salt form, formula I also includes the enolized forms of the formulas la, Ib, Ic and Id where M is hydrogen or a metal ion or ammonium ion.

Since the compounds of formula I can also contain asymmetric carbon atoms, for example, in the case of the carbon atom carrying Rj, D and A, all stereoisomeric forms are also included.

The organic substituent Q may be an inert substituent of any desired structure, with the proviso that the compounds of the formula I retain their action as HPPD inhibitors in animals. Said tests of these compounds can be carried out according to the experimental methods described herein.

Q is preferably a mono- or poly-substituted phenyl, pyridyl or heteroaryl group, especially 2-benzoyl, 2-isonicotinoyl and 2-nicotinoyl derivatives; the substitution pattern of these groups being freely selectable with the proviso that the compounds of formula 1 retain their action as HPPD inhibitors in animals.

In a particular embodiment, said HPPD inhibitors are compounds of formula I where Q is Q, where Ai or A2 are independently selected from methine, C (Rai) or N (0) | >; (where, preferably, at least one of Ai or A2 is methine, p is 0 or 1; Rai is hydrogen, Ci-C6 alkyl, hydroxy, C6-C6 alkoxy, Ci-C6 haloalkoxy, C3-C6 alkenyloxy, C3-C6 haloalkenyloxy, C3-C6 alkynyloxy, C) -C4 alkylcarbonyloxy, C] -C4 alkylsulfonyloxy, tosyloxy, alkylthioC | -C4, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 1 -C alkylamino, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 haloalkyl, formyl, cyano, halogen, phenyl or phenoxy; it being possible for the phenyl, in turn, to be substituted by Ci-C3 alkyl, haloCi-C3, alkoxyC | -C3, halogen, cyano or by nitro; or Raí is a monocyclic ring system of three to ten members or, together with Ra 2 or Ra 5, a ringed mono or bicyclic ring system which may be interrupted by oxygen, sulfur, SO, S02, NRa6, carbonyl and / or = NORa; the ring system, unless it is ringed, is linked to the carbon atom of the substituent Ai directly or by an alkylene group C | -C4, -CH = CH-, -C = C-, -CH20-, -CH2N (alkylC , -C4) -, -CH2S-, -CH2SO- or - CH2S02-, and the ring system can contain no more than two oxygen atoms and no more than two sulfur atoms, and the ring system itself can be mono -, di- or tri-substituted with Ci-C6alkyl, Ci-C6haloalkyl "C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, Ci-C6alkoxy, haloalkoxyC | -C6, C3-C6alkenyloxy, C3-alkynyloxy- C, Cι-C 6 alkyl, C 1 -C 6 haloalkylthio, C 3 -C 6 alkenylthio, C 3 -C 6 haloalkenylthio, C 3 -C 6 alkynylthio, Cι-C 4 alkyloxy-C--C 2 alkyloxy, C 1 -C 4 alkyl-alkylthioCi-C 2 alkoxycarbonylCi-C 4 -alkylthioyl C2, cyano-alkylthioCi-C4, alkylsulfinylCi-Co, haloalkylsulfinylCi-C6, alkylsulfonylCi-C6, haloalkylsulfoylCi-C6, aminosulfonyl, alkylaminosulfonylCi-C2, di (alkylC | -C2) aminosulfonyl, di (alkylC | -C4) amino, halogen, cyano, nitro, phenyl and / or benzylthio, it being possible for phenyl and benzylthio, in turn, to be substituted on the phenyl ring by C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, haloalkoxy C | -C3, halogen, cyano or by nitro and, the substituents on the nitrogen atom of the heterocyclic ring are different from halogen; or Rai is the group -X5-X7 or the group -X6-X5-X7; where X6 is a C6-C6 alkylene, C3-C6 alkenylene or C3-C6 alkynylene chain which may be mono- or polysubstituted with halogen and / or with X8, the unsaturated bonds of the chain being not directly linked to the X5 substitution; X8 is hydroxy, C6-C6 alkoxy, C3-C6 cycloalkyloxy, C6-C6 alkoxyCi-C6 alkoxy, C6-C6 alkoxyCi-Co-alkoxy-Ci-Co or alkylsulfonyloxyCi-C2; X5 is oxygen, -O (CO) -, - (CO) O-, -0 (CO) 0-, -N (C-alkyl, -C4) -0-, -0-N (CrC4 alkyl), thio, sulfinyl , sulfonyl, -S02N (C 1 -C 4 alkyl), -N (alkoxyCiC 4) S 0 2 -, -N (C 1 -C 4 alkyl) S 0 2 -, - N (C 1 alkoxy, C 2 -C 0 alkyl) S 0 2 - or -N ( alkylC, C4) -; Ra6 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylthiocarbonyl, C 1 -C 4 alkylsulfinylCi-C 4 carbonyl-Ci-C 4, alkylsulfonyl-Ci-C carbonyl-C] -C 4, C 1 -C 4 alkoxycarbonyl, alkylcarbonyl C] -C, phenylcarbonyl or phenyl, it being possible for the phenyl groups, in turn, to be substituted by Ci- C alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, C 1 -C 4 haloalkoxy, Ci-C 4 alkylcarbonyl, C | -C alkoxycarbonyl, alkylamino C | -C4, dialkylaminoC | -C4 aminosulfonyl, alkyl-SC | -C, alkyl-SO-C | -C4, alkyl-S02-C | -C, alkyl-S (0) 20-C | -C4, haloalkyl-SC, -C4, haloalkyl -SO-C | - C4, haloalkyl-S02-C | -C, haloalkyl-S (0) 20-Ci-C4, alkyl-S (0) 2NH-Ci-C4, halogen, nitro or by cyano; Ra7 is C 1 -C 4 alkyl; a2 is hydrogen, Ci-Co alkyl, C6-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, vinyl substituted with alkoxycarbonylCi-C2 or by phenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, ethynyl substituted with trimethylsilyl, hydroxy, Ci-C2alkoxy- , C 1 -C 2 alkoxycarbonyl or by phenyl, C 3 -C 4 -alicylic acid ("C 3 -C 6 cycloalkyl, C 3 -C 6 halo-substituted cycloalkyl, C 6 -C 6 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 haloalkoxy, C 3 -C 6 haloalkenyloxy, C 4 -C 4 cyanoalkoxy, C 1 -C 4 alkoxy-C 4 -C 4 alkyloxyCi-C 4 alkoxy-C 1 -C 4 alkylsulfinylCi-C 4 -alkoxyC 4 -C 4 alkylsulfonylCi-C 4 -alkoxy-Ci-C 4, alkoxycarbonylCi-C 4 -alkoxy-Ci-C 4, alkylthioC-C4, alkylsulfinylCi-C6, alkylsulfonylCi-C6, haloalkylthioCi-C6, haloalkylsulfinylCi-C6, haloalkylsulfonylC | -C6, alkoxycarbonylC i-C4-alkylthio-C i -C4, alkoxycarbonylC i -C4alkylsulfinyl-C i -C4, alkoxycarbonylC i -C4alkylsulfonyl-C i -C4, benzyl-S-, benzyl-SO-, benzyl-S02-, alkylaminoCi-C6, di-alkylaminoC2-C6, alkylaminoC |-C6-sulfonyl, di (alkylaminoCi-C) sulfonyl, benzyloxy , benzyl, phenyl, phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, it being possible for the groups containing phenyl, in turn, to be substituted by C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano or by nitro, or Ra 2 is OS-C 1 -C 4 alkyl, OSO C 1 -C 4 alkyl, OS 0 2 -C 4 alkyl, C 4, OS haloalkyl C, C 4, OSO C 1 -C 4 alkyl, OS 0 2 haloalkyl C i C 4, N (C alkyl) , -C4) -S-Ci-C4 alkyl, N (C-alkyl, -C4-SO-Ci-C4 alkyl, N (C 1 -C 4 alkyl) -S 0 2 -Ci-C 4 alkyl, cyano, carbamoyl, C 1 -C 4 alkoxycarbonyl, formyl, halogen, rholane, amino, hydroxy-C4alkyl, alkoxyCi-C4alkoxyalkyl loCi-C4, alkylCi-C4-S- alkylC | -C4, alkylCi-C -SO-alkylCi-C, alkylC | -C4-S02-alkylC | -C4, cyano-C1C4alkyl, alkylcarbonyloxyCi-C6-Ci-C4alkyl, C 1 -C 4 alkoxycarbonylCi-C 4 alkyl, C 1 -C 4 alkoxycarbonyloxyCi-C 4 alkyl, C 1 -C 4 cycloalkyl; -C4, benzoyloxyCi-C4alkyl, C2-C6-oxyranyl, alkylaminoCi-C4-Ci-C4alkyl, di (C4-alkyl) amino-C -Calkyl, alkylthiocarbonylCi-Ci2-Ci-C4alkyl or formyl-C-C4alkyl, or Ra2 is a ring system monocyclic or bicyclic or ringed from five to ten members that can be aromatic or partially saturated and can contain between 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, the ring system being linked to the pyridine ring by an alkylene groupCi -C4, -CH = CH-, -CSC-, -CH20-, -CH2N (Ci-C alkyl) -, -CH2SO- or -CH2S02-, and each ring system may contain no more than two carbon atoms. oxygen and not more than two sulfur atoms, and the ring system itself can be mono-, di- or trisubstituted with C] -C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, haloalkynylC2- C, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, mercapto, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 3 -C 6 alkenylthio, C 3 -C 6 haloalkenylthio, C 3 -C 6 alkynylthio, C 2 -C 5 alkoxyalkylthio acetylalkotithium C3-Cs, alkoxycarbonylalkylC3-C6, cyanoalkylthioC2-C4, alkylsulfamylCi-C6, haloalkylsulfinylCi-C6, alkylsulfonylCi-C6, haloalkylsulfonylC | -C6, aminosulfonyl, alkylaminosulfonylC | -C2, di (alkylC | -C2) aminosulfonyl, di (alkylC | - C4) amino, halogen, cyano, nitro, phenyl and / or benzylthio, it being possible for phenyl and benzylthio, in turn, to be substituted on the phenyl ring by C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, haloalkoxy C | -C3, halogen, cyano or by nitro and, the substituents on the nitrogen atom of the heterocyclic ring are different and halogen; or Ra2 is the group -X | -X3 or the group -X2-X | -X3; where X2 is a C6-C6 alkylene, C3-C6 alkenylene or C3-C6 alkynylene chain which may be mono- or pol-substituted with halogen and / or with X, the unsaturated bonds of the chain not being directly linked to the substituent Xi; X 4 is hydroxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 6 -C 6 alkoxyCi 6 alkoxy, C 1 -C 6 alkoxy C 6 -C 6 alkoxy or C 6 -C 6 alkylsulfonyloxy; X, is oxygen, -O (CO) -, - (CO) O-, -0 (CO) 0-, -N (C-alkyl, -C4) -0-, -0-N (CrC4 alkyl), thio, sulfinyl, sulfonyl, -S02N (C 1 -C 4 alkyl), -N (alkoxyCiC 4) S 0 2 -, -N (C 1 -C 4 alkyl) S 0 2 -, - N (C 2 -C 2 alkoxyCi-C 2 alkoxy) S 0 2 - or -N ( alkylCiC4) -; X3 and X7 are each, independently of the others, a Ci-C8 alkyl, C3-C6 alkenyl or C3-C6 alkynyl group that is mono- or polysubstituted with the following substituents: halogen, hydroxy, amino, formyl, nitro, cyano, mercapto , carbamoyl, alkoxyC (-C6, alkoxycarbonylCrC6, alkenylC2-C6, haloalkenylC2-C6, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, C3-C alkenyloxy, C3-C6 alkynyloxy, haloalkoxyCi-C6, haloalkenyloxyC3-C6, cyano-C6-alkoxy, C6-C6 alkoxyCi-C6 alkoxy -alkoxyCi-C6, alkoxyCi-C6-alkoxy-C | -C6-alkoxyCi-C6, alkylthioC | -C6-alkoCi-C6, alkylsulfinylCi-C6-alkoxyCi-C6, alkylsulfonylCi-C6-alkoxyCi-C6 , alkoxycarbonylC? -C6-alkoxyCi-C6, alkoxycarbonylCi-C6, alkylcarbonylCi-Co, alkylthioCi-C6, alkylsulfinylC | -C6, alkylsulfonylCi-C6, haloalkylthioCi-C6, haloalkylsulfinylC | -C6, haloalkylsulfonylC | -C6, oxyranyl, which can in turn , to be substituted with C 1 -C 6 alkyl, (3-oxetanyl) -oxi, which may, in turn, be substituted with C 1 -C 6 alkyl, benzylthio, benzylsulfinyl, benzylsulfonyl, alkylaminoCi-C 6, di (alkylCi-C) amino, alkylC | -C4-S (0) 20, alkylCi-C4-N (alkylCi-C4) S02-, rolne, phenyl, phenoxy, phenylthio, phenylsulfonyl and / or phenylsulfonyl; it being possible for the groups containing phenyl or benzyl, in turn, to be substituted by one or more of Ci-C6 alkyl, haloalkyl Ci-C, alkoxy C | -C6, haloalkoxy Ci-C6, halogen, cyano, hydroxy and / or nitro groups, or X3 and X7 are each, independently of the other, phenyl which may be substituted one or more times with Ci-C6 alkyl, Ci-C6 haloalkyl, C | -C6 alkoxy, C | -C6 haloalkoxy, halogen, cyano, hydroxy and / or nitro groups, or X3 and X7 are each independently of the other, C3-C-cycloalkyl, C6-C6 alkoxy or C3-C6 cycloalkyl-substituted C6-C6 alkyl, 3-oxetanyl or 3-oxetanylC1-C6alkyl; or X3 and X7 are each, independently of the other, a ring system monocyclic or bicyclic ringed from five to ten members that can be aromatic or saturated. or partially saturated and, may contain between 1 and 4 heteroatoms selected from nitrogen, oxygen and sulfur, the ring system being linked to the substituent X) or X5 either directly or via an alkylene C group; -C4, alkenylC2-C4-C 1 -C 4 alkylene, C 2 -C 4 alkynyl-Ci-C 4 alkylene, -N (C 1 -C 4 alkyl) -C 1 -C 4 alkylene, - SO-alkylene C | -C 4 or -S02- alkyleneC | -C, and each ring system may contain no more than two oxygen atoms and no more than two sulfur atoms, and the ring system itself may be mono-, di- or tri-substituted with Ci-C6alkyl, haloalkyl C | -C6, C2-C6 alkenyl, haloalkenyl C2- C ("C2-C6 alkynyl, haloalkynylCi-Co, C6-C6 alkoxy, hydroxy, C6-C6 haloalkoxy, C3-C alkenyloxy, C3-C6 alkynyloxy, mercapto, Ccy-C6 alkylthio, C6-C haloalkyl, C3-C6 alkenylthio, C3-C6 haloalkenylthio, C3-alkynylthio -C6, alkoxyalkylthio-C2-Cs, acetylalkylC3-C5, alkoxycarbonylalkylC4-C6, cyanoalkylthioC2-C4, alkylsulfinylCi-C6, haloalkylsulfinylC | C, alkylsulfonylC | -C6, haloalkylsulfonylCi-C, aminosulfonyl, alkylaminosulfonylCi-C2, di (alkylC | -C 2) -aminosulfonyl, di (C 1 -C 4 alkyl) amino, halogen, cyano, nitro, phenyl and / or with benzylthio, it being possible for phenyl and benzylthio, in turn, to be substituted on the phenyl ring with C 1-4 alkyl C3, haloalkylC | -C3, alkoxyC | -C3, haloalkoxyCi-Cs, halogen, cyano or with nitro, and the substituents on the nitrogen atom of the heterocyclic ring are different from halogen; Ra3 is hydrogen, Ci-C6alkyl, haloalkylC | - C6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, haloalkynylC2-C6, C3-C6 cycloalkyl, a lcoxiC | -C6, haloalkoxyCi-Co, alkylthioC | -C6, alkylsulfinylCi-C6, alkylsulfonylCi -C6, alkylaminoCi-C6, di-alkylaminoC2-C6, alkylaminoCi-Cft-sulfonyl, di-alkylaminoC] -C6sulfonyl, phenyl, phenylthio, phenylsulfinyl, phenylsulfonyl or phenoxy, being possible for the groups containing phenyl, in turn, being substituted by C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano or by nitro, or Ra 3 is -N (C 1 -C 4 alkyl) -S-C alkyl; -C 4, -N (C 1 -C 4 alkyl) -SO-C 1 alkyl, -C 4, -N (C 1 -C 4 alkyl) -S 0 2 -Ci-C 4 alkyl, cyano, halogen, amino, C 4 -C 4 alkoxyCi-C 4 alkyl, C 1 -C alkyl S-alkylC | -C4, alkylC | -C4-SO- alkylCi-C4 or alkylCi-C4-S02-alkylC | -C4; Ra is hydrogen, alkyiCi-C6, hydroxy, C6-C6 alkoxy, C6-C6 haloalkoxy, C3-C alkenyloxy, C3-C6 haloalkenyloxy, C3-C6 alkynyloxy, C-C4 alkylcarbonyloxy, C-C4 alkylsulfonyloxy, tosyloxy, alkylthioCi. C 4, alkylsulfinyl C] -C 4, alkylsulfonylCi-C 4, alkylamino C | -C 4, di-C 1 -C 4 alkylamino, alkoxycarbonylCi-C 4, haloalkyl Ci-C 4, formyl, cyano, halogen, phenyl or phenoxy; it being possible for the phenyl, in turn, to be substituted by C 1 -C 3 alkyl, haloalkyl C | -C3, alkoxyC | -C3, halogen, cyano or by nitro; or Ra4 is a ten-membered monocyclic ring system or, with Ra3, a ringed bicyclic ring system which may contain between 1 and 4 heteroatoms selected from nitrogen, oxygen and sulfur, the ring system, unless ringed, is linked to the ring containing substituent A directly or by an alkylene group C 1 -C 4, -CH = CH-, -C = C-, - CH 2 -, -CH 2 N (C 1 -C 4 alkyl) -, -CH 2 S-, -CH 2 SO- or -CH 2 S02 -, and the ring system can contain no more than two oxygen atoms and no more than two sulfur atoms and the ring system itself can be mono-, di- or tri-substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, alkenyl C2-C6, C2-C6 haloalkenyl, C2-C6 alkynyl, haloalkynylC-C6, C6-C6 alkoxy, Ci-C6 haloalkoxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C12-C6 alkylthio, haloalkylthioCi-C6, C3-C6 alkenylthio, haloalkenylthioC3-Qi , C 3 -C 6 alkynylthio, C 1 -C 4 alkyloxy-C 1 -C 2 alkoxy, C 1 -C 4 alkylcarbonyloxy C 2 -C 4 alkoxycarbonyl C 1 -C 4 alkylthioCi-C 2, cyano-alkylthioCi-C 4, alkyls ulfinylCi-C6, haloalkylsulfinylCi-Co, alkylsulfonylCi-C6, haloalkylsulfonylCi-Co, aminosulfonyl, alkylaminosulfonylC | -C2, di (alkylC | -C2) aminosulfonyl, di (alkylC | -C4) amino, halogen, cyano, nitro, phenyl and / or benzylthio, being possible for the phenyl and benzylthio, in turn, to be substituted on the phenyl ring by C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano or C 1 -C 3 alkyl , C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano or with nitro, and the substituents on the nitrogen atom of the heterocyclic ring are different from halogen; Ra 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, C 6 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 6 alkylthioCr, C 6 -C 6 alkylsulfonyl, C 2 -C 6 alkylsulfonyl Co, haloalkylthioCi-Co, haloalkylsulfinylC | -C6, haloalkylsulfonylCi-C6, alkylaminoCi-C6, di-alkylaminoC2-C6, alkylaminosulphonylC | -C6, di-alkylaminosulfonylC2-C6, phenyl, phenylthio, phenylsulfinyl, phenylsulphonyl or phenoxy, being possible for phenyl, in turn, being substituted by Ci-C3alkyl, haloalkylC] -C3, alkoxyC | -C3, haloalkoxyC | -C3, halogen, cyano or with nitro, or Ra5 is -N (alkyl CrC4) -S-alkylCiC4, - N (C 1 -C 4 alkyl) -SO- C 1 -C 4 alkyl, -N (C 1 -C 4 alkyl) -S 0 2 -Ci-C 4 alkyl, cyano, halogen, amino, C 1 -C 4 alkoxyC 1 -C alkyl, C 1 -C 4 alky -S-C 1 -C 4 alkyl, C 1 -C 4 alkyl-SO 4 -Ci 4 alkyl, or C 1 -C 4 alkyl-S 0 2 C 1 -C 4 alkyl, and the pharmaceutically acceptable salts / N-oxides / isomers / enantiomers of these compounds.

The alkyl groups appearing in the above definitions of the substituents can be straight or branched chain and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. The alkoxy, alkenyl and alkynyl radicals are derived from the aforementioned alkyl radicals. The alkenyl and alkynyl groups can be mono- or poly-unsaturated. The alkoxy, alkenyl and alkynyl radicals are derived from the aforementioned alkyl radicals. The alkenyl and alkynyl groups can be mono- or poly-unsaturated. Alkoxy is, for example, methoxy, epoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. Alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; preferably, methoxycarbonyl or ethoxycarbonyl.

Halogen is generally fluorine, chlorine, bromine or iodine. Halogen is also understood as the combination with other groups, haloalkyl or halophenyl.

Haloalkyl groups having a chain length between 1 and 6 carbon atoms are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2-fluoroethyl, -chloroethyl, 2-fluoroprop-2-yl, pentafluoroethyl, 1-l-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl, pentafluoroethyl, heptafluoro-n -propyl and perfluoro-n-hexyl.

The alkenyl and alkynyl groups can be mono- or poly-unsaturated so that the alkyl, alkenyl and alkynyl chains having one or more double or triple bonds are also included.

Alkenyl is, for example, vinyl, allyl, isobuten-3-yl, CH2 = CH-CH2-CH = CH-, CH2 = CH-CH2-CH2-CH = CH- or CH3-CH = CH-CH2-CH = CH-. A preferred alkynyl is, for example, propargyl and a preferred allynyl is CH 2 = C = CH 2 -.

An alkylene chain can also be substituted by one or more Ci-C3 alkyl groups, especially methyl groups. Said alkylene chains and alkylene groups are preferably unsubstituted. The same applies to all groups containing C3-C cycloalkyl, C3-C5 oxacycloalkyl, C3-C5 cycloalkyl, dioxacycloalkyl C3, C3-C4 dithiacycloalkyl or C3-C4 oxatyacycloalkyl occurring, for example, as part of oxygen-containing heterocyclic ring systems and Sulfur of radicals Raí and Ra2.

It should be understood that a C 1 -C 4 alkylenecarbon, C 3 -C 4 alkenylene or C 2 -C 4 alkynylene bridge that can be interrupted with oxygen, -N (C 1 -C 4 alkyl), sulfur, sulfinyl and / or sulfonyl, or on X 2 or X 6 referring to an alkylene C chain | -C6, C3-C6 alkenylene or C3-C6 alkynylene which may be mono- or poly-substituted with halogen and / or with X or X8, and where the unsaturated bonds of the chain are not directly linked to the substituent Xi or X5, is, for example, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH (CH3) -, -CH2CH (CH3) -, -CH2CH (CH3) CH2-, - CH2CH (C1) CH2-, - CH2CH (OCH3) CH2-, -CH20-, - OCH2-, -CHjOCfL: -, -OCH2CH2-, - OCH2CH2CH2-, -CH2OCH2CH2-, - CH2OCH (CH3) CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2 -, - CH2S-, -CH2SCH2-, - CH2S (0) CH2-, -CH2S02CH2-, -CH2SCH2CH2-, -CH2S (0) CH2CH2-, - CH2S02CH2CH2-, -CH2S02NH-, -CH2N (CH3) S02CH2CH2-, -N (S02Me) CH2CH2-, -CH2C (0) NH- or -CH2NHC (0) CH2-. A C2-C4 alkylene chain that may not be interrupted or interrupted by oxygen should be considered as if, for example, -CH = CH-CH2-, - CH = CH-Cl-I2CH2- or -CH == CHCH2OCH2-, and an alkynylene C2-C4 chain which may not be interrupted or interrupted with oxygen should be considered as if it were, for example, -C = C-, -C = CCH2-, -C = CCH20-, -C = CCH2OCH2- or -OC = CCH2-.

A mono- or bicyclic ring system of three to ten Rai or Ra2 members, which may be interrupted once or up to three times with a group selected from oxygen, sulfur, S (O), S02, N (Ra6), carbonyl and C (= NORa7) and which is linked to the carbon atom of the substituent Ai or to the group Qi or Q2 either directly or via an alkylene bridge Ci-C4, alkenylene C | -C4 or alkynylene C2-C4 which may be interrupted by oxygen, -N (Ci-C4 alkyl) -, sulfur, sulfinyl and / or sulfonyl , it should be considered as, for example, 1-methyl-β-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-propyl-1H-pyrazol-3-yl, 1H-pyrazole -3-yl, l, 5-dimethyl-lH-pyrazol-3-yl, 4-chloro-l-methyl-lH-pyrazol-3-yl, lH-pyrazol-l-yl, 3-methyl-lH-pyrazole -l -yl, 3,5-dimethyl-lH-pyrazol-1-yl, 3-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methyl-5-isoxazolyl, 5-isoxazolyl, lH-pyrrole-2 ilo, 1-methyl-lH-pyrrol-2-yl, lH-pyrrol-l-yl, l-methyl-lH-pyrrol-3-yl, 2-furanyl, 5-methyl-2-furanyl, 3-furanyl, 5- methyl-2-thienyl, 2-thienyl, 3-thienyl, l-methyl-lH-imidazol-2-yl, lH-imidazol-2 -yl, 1-methyl-lH-imidazol-4-yl, l-methyl-lH-imidazol-5-yl, 4-methyl-2-oxazolyl, 5-methyl-2-oxazolyl, 2-oxazolyl, 2-methyl -5-oxazolyl, 2-methyl-4-oxazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-thiazolyl, 2-methyl-5-thiazolyl, 2-methyl-4-thiazolyl, 3 -methyl-4-isothiazolyl, 3-methyl-5-isothiazolyl, 5-methyl-3-isothiazolyl, 1-methyl-1H-1, 2,3-triazol-4-yl, 2-methyl-2H-1, 2 , 3-triazol-4-yl, 4-methyl-2H-1, 2,3-triazol-2-yl, 1-methyl-1H-1, 2,4-triazol-3-yl, 1, 5-dimethyl -lH-l, 2,4-triazol-3-yl, 3-methyl-lH-l, 2,4-triazol-l-yl, 5-methyl-lH-l, 2,4-triazol-l-yl , 4,5-dimethyl-4H-l, 2,4-triazol-3-yl, 4-methyl-4H-1, 2,4-triazol-3-yl, 4H-I, 2,4-triazole-4 -yl, 5-methyl-l, 2,3-oxadiazol-4-yl, 1,3-oxadiazol-4-yl, 3-methyl-l, 2,4-oxadiazol-5-yl, 5-methyl -l, 2,4-oxadiazol-3-yl, 4-methyl-3-furazanyl, 3-furazanyl, 5-methyl-l, 2,4-oxadiazol-2-yl, 5-methyl-l, 2,3 -thiadiazol-4-yl, l, 2,3-thiadiazol-4-yl, 3-methyl-l, 2,4-thiadiazol-5-yl, 5-methyl-l, 2,4-thiadiazol-3-yl , 4-methyl-l, 2,5-thiadiazol-3-yl, 5-me til-l, 3,4-thiadiazol-2-yl, l-methyl-lH-tetrazol-5-yl, lH-tetrazol-5-yl, 5-methyl-lH-tetrazol-l-yl, 2-methyl- 2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl, 5- methyl-2H-tetrazol-2-yl, 2H-tetrazol-2-yl, 2-pyridinyl, 6-methyl-2-pyridinyl, 4-pyridinyl, 3-pyridinyl, 6-methyl-3-pyridazinyl, 5-methyl- 3-pyridazinyl, 3-pyridazinyl, 4,6-dimethyl-2-pyrimidinyl, 4-methyl-2-pyrimidinyl, 2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 2-chloro-4-pyrimidinyl, 2,6- dimethyl-4-pyrimidinyl, 4-pyrimidinyl, 2-methyl-5-pyrimidinyl, 6-methyl-2-pyrazinyl, 2-pyrazinyl, 4,6-dimethyl-l, 3,5-triazin-2-yl, 4, 6-dichloro-l, 3,5-triazin-2-yl, l, 3,5-triazin-2-yl, 4-methyl-l, 3,5-triazin-2-yl, 3-methyl-l, 2,4-triazin-5-yl, 3-methyl-l, 2,4-triazin-6-yl, where each R 2 is methyl, each R 27 is independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or trifluoromethyl, and X 9 is oxygen or sulfur.

Another monocyclic or bicyclic ring system (fused) which is formed, for example, by two adjacent substituents Ra1 and Ra2 or Ra1 and Ra5 and which is not interrupted or interrupted one to three times by a group selected from oxygen, sulfur , S (O), SO2, -N (Ra) -, carbonyl and C (= NORa7) and that may be additionally substituted with one or more substituents, it should be considered as if it were, for example, a ringed ring system, bidentate of the formula where, especially, R 6 is hydrogen, halogen, C) -C alkyl, haloalkyl C) -C 4, C 1 -C 4 alkoxy or C 1 -C 4 alkylthio; R47 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy; and Rs0, R51, R52, R53, R54, R55, R56, R57, R5! and R 5g are hydrogen or C 1 -C 4 alkyl; and X10 is oxygen or NOR59.

In the art, a number of HPPD inhibitors of formula I are described.

In a particular embodiment of the invention, the HPPD inhibitor comprises the compound of the formula I wherein: T is YOU Ri and R2 are hydrogen; A is alkyleneCi-C2; D and E together are C2-C3 alkylene; Q is Qi, where Ai is metina, CRai or but perfectly p is O; Rai is hydrogen, C 1 -C 4 alkyl, hydroxy, C 6 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 alkenyloxy, C 6 haloalkenyloxy, C3-C6 alkynyloxy, alkylcarbonyloxyCi-C4, alkylsulfonyloxyC | -C4, tosyloxy, alkylthioC | -C4, alkylsulfinylC | -C4, alkylsulfonylC | -C4, alkylaminoC | -C4, di-alkylaminoC | -C4, alkoxycarbonylC | -C4, haloalkylC | -C4, formyl, cyano, halogen, phenyl or phenoxy; it being possible for phenyl, in turn, to be substituted with alkylC | -C3, haloalkylC- C3, alkoxyC | -C3, haloalkoxyC | -C3, halogen, cyano or with nitro; Ra2 is hydrogen, Ci-C6alkyl, haloalkylC-C6, alkenylC2-C6, haloalkenylC2-C6, vinyl substituted with alkoxycarbonyl Ci-C2 or with phenyl, alkynylC2-C6, haloalkynylC2-C6, ethynyl substituted with trimethylsilyl, hydroxy, alkoxyC | - C2, alkoxycarbonylC] -C2 or with phenyl, C3-C6 allynyl, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, C6-C6 alkoxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, haloalkoxyCi-C6, haloalkenyloxyC3-C6, cyano-alkoxyCi- C4, C 1 -C 4 alkoxy-C 4 alkoxy, C 1 -C 4 alkylthio-C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfinyl-C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl-C 1 -C 4 alkoxy, C 1 alkoxycarbonyl | -C 4 -alkoxy-C | -C4, alkylthioCi-C6, alkylsulfinylCi-Co, alkylsulfonylCi-C6, haloalkylthioCi-Co, haloalkylsulfinylCi-C6, haloalkylsulfonylCi-Co, alkoxycarbonylCi- C4alkylthio-C i C4, alkoxycarbonylCi-C4-alkylsulfinyl-C] -C4, alkoxycarbonylC | -C 4 -alkylsulfonyl- C 1 -C 4, benzyl-S-, benzyl-SO-, benzyl-S02-, alkylaminoC-C6, di-alkylaminoC2-C6, alkylaminosulfonylCi-C6, di (alkylaminoCi-C6) sulfonyl, benzyloxy, benzyl, phenyl, phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, it being possible for the groups containing phenyl, in turn, to be substituted with Ci-C3 alkyl, haloalkylC | -C3, alkoxyCi-C3, haloalkoxyCi-C3, halogen, cyano or with nitro, or Ra2 is OS-alkylC | -C4, OSO-alkylC | -C4, OS02-alkylC) -C4, OS- haloalkylCrC4, OSO-haloalkylC | -C4, OS02-haloalkylC | -C4, N (alkylCi-C4) -S-alkylCi-C4, N (alkylC | -C4) -SO-alkylCi-C4, N (alkylC | -C4) -S02-alkylC | -C4, cyano, carbamoyl, alkoxycarbonylC | -C 4, formyl, halogen, rholene, amino, hydroxyCi-C 4 alkyl, C 1 -C 4 alkoxy- C 1 -C 4 alkyl, C 1 -C 4 alkyl-C 1 -C 4 alkyl, C 1 -C 4 alkyl- SO 4 C 1 -C 4 alkyl, C alkyl -C4-S02- Ci- C4 alkyl, cyano-Ci- C4 alkyl, alkylcarbonyloxyCi-C6-Ci- C4 alkyl, alkoxycarbonylC | -C4- alkylC | -C4, alkoxycarbonyloxyC | -C4-alkylC | -C4, rodanoC | -C4-alkyl-Ci-C4, benzoyloxy- C1-C4alkyl, C6-oxyranyl, C4-C4alkylamino-Ci-C4alkyl, di (C 1 -C 4 alkyl) amino-C 1 -C 4 alkyl, alkylthiocarbonyl C 1 -Ci 2 -alkylCi-C 4 or fotT nyl-Ci- C 4 alkyl, or Ra 2 is the group -X1 -X3 or the group -X2-X | -X3; where X |, X2 and X3 are as defined above; Ra3 and Ra4 are hydrogen and Ras is as defined above.

In yet another embodiment of the invention, the HPPD inhibitor comprises a compound of formula 1 wherein: T is T,; Ri and R2 are hydrogen, A is methylene, D and E together are ethylene, Ai is = N- (0) P; where p is 0; Q is Qi, Ra3 and Ra4 are hydrogen, Ra5 is haloalkylCi-C3, especially trifluoromethyl, and Ra2 is alkoxyC | -C4-alkoxy-C | -C 4 -C 4 alkyl, especially methoxyethoxymethyl.

HPPD inhibitor compounds are well known in the art and there are numerous tests that can be used to identify the ability of said test compound to inhibit HPPD. For example, in vitro screening assays may be used as described in the examples of the present application or, alternatively, methods such as that described in Example 11 of WO 02/46387 may be used where a known HPPD enzyme is selected and applies a test inhibitor compound.

Even in another embodiment of the invention, the HPPD inhibitor is 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-Cyclohexanedione (compound 2). The test compound can be interchanged with formula II). It will be appreciated that 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione (compound 2) can exist in one or more tautomeric forms, one of the which is shown in formula (II) (ie, compound 2) interconvert rapidly by keto-enol tautomerism.

(Compound 2) It is understood that the invention includes the use of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-Cyclohexanedione in any of said tautomeric forms or mixtures thereof. 2- (2-Nityl-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione is acidic and rapidly forms salts with a wide variety of bases.

Particularly suitable salts of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione, suitable for use as active ingredients in pharmaceutical compositions according to the invention, include, for example, pharmaceutically basic addition salts acceptable, for example, alkali metal salts (such as potassium or sodium), alkaline earth metal (such as calcium or magnesium) and ammonium salts, and salts with organic bases that form physiologically acceptable cations (such as salts with methylamine, dimethylamine, methylamine) , piperidine and morpholine).

The 2- (2-Nitro-4-trifluoromethylbenzoyl) -l, 3-cyclohexanedione can be obtained by conventional methods known from organic chemistry for the production of structurally analogous materials.

In this way, for example, 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione can be conveniently obtained by the reaction of 2-nitro-4-chloride.

Influoromethylbezoyl with cyclohexane-l, 3-dione, in the presence of acetone cyanohydrin and a suitable base such as triethyl sheet.

The same starting 2-nitro-4-trifluoromethylbenzoyl chloride can be obtained from the corresponding benzoic acid, for example, by reaction with thionyl chloride or oxalyl chloride as described in Reagents for Organic Synthesis, (J. Wiley and Sons, 1967; editors: Fieser LF and Fieser M., Vol 1, pages 767-769) and, in general, used without other special purification.

Similarly, 2-nitro-4-trifluoromethylbenzoic acid can be obtained, for example, as described by Haupstein et al., In J. Amer. Chem. Soc, 1954, 76, 1051, or by one of the general methods well known to the person skilled in the art.

In another embodiment of the invention, the HPPD inhibitor or precursor is a compound having the structure illustrated in Table A below.

Table A Structure Number: compound 3. 01 In addition to the compounds described herein, it is also possible to use a compound that is a precursor of a HPPD inhibitor compound.

A "precursor" is a compound that, in itself, is not an HPPD inhibitor but is metabolized to produce an HPPD inhibitor for use in accordance with the present invention.

For example, the compound illustrated as compound 3.01 in Table A above is a precursor of the compound illustrated as compound 3.15.

Thus, throughout the description, "HPPD inhibitor" includes those compounds that are capable of inhibiting HPPD in animals and any of the precursor compounds thereof that are capable of being metabolized in the animal to produce the HPPD inhibitor compound.

It will be appreciated that the alternative steps of the tyrosine catabolic pathway can be further inhibited or as an alternative to the inhibition of HPPD. For example, inhibitors of "upstream" HPPD enzymes / compounds may be used in said route, such as, for example, tyrosine aminotransferase and / or similar inhibitors of "downstream" enzymes / compounds of HPPD may be used in said route, such as example, homogentisic acid oxidase. The present invention further provides the use as described above, wherein said medicament is administered in combination with an anti-inflammatory agent.

The present invention further provides the use as described above, wherein said medicament comprises an anti-inflammatory agent.

The present invention further provides the use as described above, wherein the medicament comprises a first HPPD inhibitor and another HPPD inhibitor and, wherein said first inhibitor is different from the other inhibitor and wherein said inhibitors are present in a suitable amount to treat and / or prevent depression and / or treat in an animal, the withdrawal syndrome associated with an addictive drug that produces associative learning disorders dependent on dopamine in said animal. In a particular embodiment, said first and second HPPD inhibitor is selected from the inhibitor described above.

In yet another embodiment, said first and / or second compound comprises a precursor compound.

Even in another aspect of the invention, a kit is provided comprising a pharmaceutically acceptable amount of a first HPPD inhibitor and another HPPD inhibitor, wherein said first inhibitor is different from the other. In a particular embodiment, said first and second HPPD inhibitor are selected from an inhibitor described above and wherein said inhibitors are present in a suitable amount to treat and / or prevent depression and / or treat in an animal, the withdrawal syndrome associated with an addictive drug that produces associative learning disorders dependent on dopamine in said animal. In another embodiment, said first inhibitor comprises 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-Cyclohexanedione (compound 2). In yet another embodiment, said first inhibitor comprises the compound lused as 3.22 as described above.

Now the invention will be described by the following non-limiting examples and the Figure in which: Figure 1 is a representation of a part of a route that indicates the metabolism of tyrosine.

EJ EMPLOS Example 1 Illustration of the increase in levels and replacement of dopamine as a mechanism for the treatment / prevention of depression and treatment of the withdrawal syndrome associated with abstinence from an addictive drug such as cocaine.

A dose of 0.1 mg / kg of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione was orally administered to 10 mice.

As a control, 10 mice were given an oral dose with the vehicle for dosing.

After 24 hours, the tyrosine levels in plasma were identified. Dopamine levels and dopamine turnover were also analyzed.

The results were that the mice dosed with 2- (2-Nitro-4-Tlifl-Lioromethylbenzoyl) -1,3-Cyclohexanedione had high levels of tyrosine in plasma.

In addition, dopamine increased up to 16% and dopamine turnover increased by up to 27%, compared to the mean of the controls.

Example 2 They were administered to 10 mice, an oral dose of 0.1 mg / Kg of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-Cyclohexanedione.

As a control, an oral dose was administered to 9 mice with the dosing vehicle.

After 6 hours, the tyrosine levels in plasma were identified. Dopamine levels and turnover were also analyzed.

The results were that mice given a dose of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione had high levels of tyrosine in plasma.

In addition, dopamine increased up to 15% and dopamine turnover increased up to 15%, compared to the mean of the controls.

Example 3 Oral doses of 2 mg / g of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione were administered to 10 rats.

As a control, an oral dose was administered to 10 rats with the dosing vehicle.

After 24 hours, the tyrosine levels in plasma were identified. Dopamine levels and dopamine turnover, and noradrenaline levels were also analyzed.

The results were that the rats that received the dose of 2- (2-Nitro-4-Tri-lluoi-O -methylbenzoyl) -l, 3-Cyclohexanedione had high levels of tyrosine in plasma.

In addition, dopamine turnover increased by 25% in the treated group compared to the control group.

In addition, norepinephrine increased by up to 76% and 21% in the cerebral cortex and hypothalamus of treated rats compared to the mean of the controls.

Example 4 Stimulatory effect analysis of HPPD inhibitors as a mechanism for the treatment of withdrawal syndrome associated with an addictive drug such as nicotine.

Twelve doses of 2 mg / kg of 2- (2-Nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione were administered to 12 rats.

As a control, oral doses were administered to 12 rats with the dosing vehicle.

After 4 hours, each animal was placed in an activity cage for 1 hour, provided with an automatic activity monitoring system with infrared rays to determine activity and mobility.

The analysis of activity data indicated that the average breeding counts, central breeding counts and breeding time increased by 91%; 63% and 79%, respectively, compared to the control group. In addition, the counts of activity, active time and time in movement, decreased by approximately 43%, 27% and 49%, respectively, when compared with the control group. The increase in breeding activity indicated that the test substance had a mild stimulating effect on its behavior. The additional time spent in breeding made the animals spend less time in movement, which indicates why the mobility indicators decreased.

Claims (25)

1. CLAIMS 1 . The use of at least one compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (1-1 PPD) in an animal, in the manufacture of a medicament for use in the treatment and / or prevention of depression. 2. The use according to claim 1 characterized in that said medicament comprises a compound selected from the group consisting of: compound 1; 2 and 3.223. The use according to claim 1 or 2 characterized in that said medicament comprises the compound illustrated as compound 1. 4. The use according to any of the preceding claims, characterized in that said medicament comprises a selective inhibitor of serotonin reuptake (1SRS) and / or a tricyclic (tricyclic) antidepressant. 5. The use according to claim 4 characterized in that said SSRI is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline or mixtures thereof and said tricyclic is selected from the group consisting of: amitriptyline, clomipramine, Dosulepin, Amitriptyline, Clomipramine, Dosulepine, Dotiepin, Doxepin, Maprotiline, Mianserin, Trazodone, Trimipramine, Amoxapine, Imipramine, Lofepramine and Nortriptyline or mixtures thereof. 6. A kit characterized in that it comprises a pharmaceutically effective amount of a compound selected from the group consisting of: Compound 1; 2 and 3.22 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a selective inhibitor of serotonin reuptake and / or a tricyclic antidepressant and a means for administering it to an animal. 7. A pharmaceutical composition characterized in that it comprises, as an active ingredient, a pharmaceutically effective amount of a compound selected from the group consisting of compound 1; 2 and 3.22 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a selective serotonin reuptake inhibitor and / or a tricyclic antidepressant together with a pharmaceutically acceptable diluent or carrier. 8. A pharmaceutical composition according to claim 7, characterized in that said SSRI is selected from the group consisting of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline or mixtures thereof and said tricyclic is selected from the group consisting of: amitriptyline, clomipramine , Dosulepin, Dotiepin, Doxepin, Maprotiline, Mianserin, Trazodone, Trimipramine, Amoxapine, Imipramine, Lofepramine and Nortriptyline or mixtures thereof. 9. The use of at least one compound capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal in the manufacture of a medicament to be used in the treatment of the withdrawal syndrome associated with an addictive drug that produces, in said animal, associative learning disorders dependent on dopamine. 10. The use according to claim 9 characterized in that said addictive drug is a drug selected from the group consisting of: cocaine, amphetamine, opiate, nicotine, ethanol, tetrahydrocannabinol and phencyclidine. The use according to claim 10, characterized in that said medicament comprises a compound selected from the group illustrated as compound 1; 2 and 3.22. 12. The use according to any of claims 9 and 11 characterized in that the medicament comprises another compound which is also capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal. The use according to any of claims 9 to 12, characterized in that said medicament comprises a nicotine replacement therapy. 1 . The use according to any of claims 9 to 13 characterized in that said medicament comprises bupropion. The use according to any of claims 9 to 14, characterized in that said medicament is used together with a nicotine replacement therapy.16. The use according to any of claims 9 to 15 characterized in that said medicament is used together with bupropion. 17. A kit characterized in that it comprises a pharmaceutically effective amount of a compound selected from the group consisting of compound 1; 3.22; and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a nicotine replacement therapy and / or bupropion and a medium for administration to an animal. 18. A pharmaceutical composition characterized in that it comprises as active ingredient a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1, 3.22 and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a nicotine replacement therapy and / or bupropion together with a pharmaceutically acceptable diluent or carrier. 19. A pharmaceutical composition according to claim 7, 8 and 18 characterized in that it has a form suitable for oral or parenteral administration. 20. A pharmaceutical composition according to claim 19 characterized in that it has a pleasant flavor form suitable for the oral administration selected from the group consisting of: tablets; pills; hard capsules; aqueous suspensions; oily suspensions; emulsions; dispersible powders; dispersible granules; syrups and elixirs twenty-one . A pharmaceutical composition according to claim 19 or 20 characterized in that it is intended for oral use and has the form of hard or soft gelatin capsules. 22. A pharmaceutical composition as claimed in claim 19 characterized in that it has the form suitable for parenteral administration. 23. A method for treating and / or preventing depression characterized in that it comprises administering to an animal, a pharmaceutically effective amount of a compound selected from the group consisting of: Compound 1; 2; and 3.22 or a composition according to any of claims 7, 8, 18 and 22. 24. A method for treating an animal suffering from withdrawal syndrome caused by addiction to a drug that is responsible for the development of associative learning disorders dependent on dopamine in said animal, characterized in that it comprises administering to said animal a pharmaceutically effective amount of a compound selected from the group consisting of: compound 1; 3.22 and 2 or a composition according to any of claims 7, 8, 18 to 22. 25. A method according to claim 23 or 24 characterized in that said animal is a human being.